Showing papers by "Charlie Norwood VA Medical Center published in 2014"
TL;DR: Evidence indicates there is an optimal level of NRG/ ERBB signaling in the brain and deviation from it impairs brain functions, and NRGs/ERBBs and downstream signaling pathways may provide therapeutic targets for specific neuropsychiatric symptoms.
442 citations
Paris Descartes University1, French Institute of Health and Medical Research2, University of Texas Southwestern Medical Center3, Brigham and Women's Hospital4, Charlie Norwood VA Medical Center5, University of Kansas6, University of Paris7, University of Texas MD Anderson Cancer Center8, University of Verona9
TL;DR: It is found that the tumor suppressors TSC1 and TSC2, defects in which underlie the genetic disease Tuberous Sclerosis Complex, drive the mTOR-dependent autophagosomal destruction of the transcriptional activator YAP.
Abstract: Genetic studies have shown that the tuberous sclerosis complex (TSC) 1–TSC2–mammalian target of Rapamycin (mTOR) and the Hippo–Yes-associated protein 1 (YAP) pathways are master regulators of organ size, which are often involved in tumorigenesis. The crosstalk between these signal transduction pathways in coordinating environmental cues, such as nutritional status and mechanical constraints, is crucial for tissue growth. Whether and how mTOR regulates YAP remains elusive. Here we describe a novel mouse model of TSC which develops renal mesenchymal lesions recapitulating human perivascular epithelioid cell tumors (PEComas) from patients with TSC. We identify that YAP is up-regulated by mTOR in mouse and human PEComas. YAP inhibition blunts abnormal proliferation and induces apoptosis of TSC1–TSC2-deficient cells, both in culture and in mosaic Tsc1 mutant mice. We further delineate that YAP accumulation in TSC1/TSC2-deficient cells is due to impaired degradation of the protein by the autophagosome/lysosome system. Thus, the regulation of YAP by mTOR and autophagy is a novel mechanism of growth control, matching YAP activity with nutrient availability under growth-permissive conditions. YAP may serve as a potential therapeutic target for TSC and other diseases with dysregulated mTOR activity.
169 citations
TL;DR: A complete understanding of the signaling events regulating aldosterone biosynthesis may allow the identification of novel targets for therapeutic interventions in hypertension, primary aldosteronism, congestive heart failure, renal disease, and other cardiovascular disorders.
Abstract: Aldosterone is a steroid hormone synthesized in and secreted from the outer layer of the adrenal cortex, the zona glomerulosa. Aldosterone is responsible for regulating sodium homeostasis, thereby helping to control blood volume and blood pressure. Insufficient aldosterone secretion can lead to hypotension and circulatory shock, particularly in infancy. On the other hand, excessive aldosterone levels, or those too high for sodium status, can cause hypertension and exacerbate the effects of high blood pressure on multiple organs, contributing to renal disease, stroke, visual loss, and congestive heart failure. Aldosterone is also thought to directly induce end-organ damage, including in the kidneys and heart. Because of the significance of aldosterone to the physiology and pathophysiology of the cardiovascular system, it is important to understand the regulation of its biosynthesis and secretion from the adrenal cortex. Herein, the mechanisms regulating aldosterone production in zona glomerulosa cells are discussed, with a particular emphasis on signaling pathways involved in the secretory response to the main controllers of aldosterone production, the renin-angiotensin II system, serum potassium levels and adrenocorticotrophic hormone. The signaling pathways involved include phospholipase C-mediated phosphoinositide hydrolysis, inositol 1,4,5-trisphosphate, cytosolic calcium levels, calcium influx pathways, calcium/calmodulin-dependent protein kinases, diacylglycerol, protein kinases C and D, 12-hydroxyeicostetraenoic acid, phospholipase D, mitogen-activated protein kinase pathways, tyrosine kinases, adenylate cyclase, and cAMP-dependent protein kinase. A complete understanding of the signaling events regulating aldosterone biosynthesis may allow the identification of novel targets for therapeutic interventions in hypertension, primary aldosteronism, congestive heart failure, renal disease, and other cardiovascular disorders.
128 citations
TL;DR: Sera from MG patients with agrin antibodies were able to recognize recombinant agrin in conditioned media and in transfected HEK293 cells and inhibited the agrin-induced MuSK phosphorylation and AChR clustering in muscle cells, indicating that agrin is another autoantigen in patients with MG and agrin autoantibodies may be pathogenic through inhibition of agrin/LRP4/MuSK signaling at the NMJ.
Abstract: To determine if patients with myasthenia gravis (MG) have antibodies to agrin, a proteoglycan released by motor neurons and is critical for neuromuscular junction (NMJ) formation, we collected serum samples from 93 patients with MG with known status of antibodies to acetylcholine receptor (AChR), muscle specific kinase (MuSK) and lipoprotein-related 4 (LRP4) and samples from control subjects (healthy individuals and individuals with other diseases). Sera were assayed for antibodies to agrin. We found antibodies to agrin in 7 serum samples of MG patients. None of the 25 healthy controls and none of the 55 control neurological patients had agrin antibodies. Two of the four triple negative MG patients (i.e., no detectable AChR, MuSK or LRP4 antibodies, AChR-/MuSK-/LRP4-) had antibodies against agrin. In addition, agrin antibodies were detected in 5 out of 83 AChR+/MuSK-/LRP4- patients but were not found in the 6 patients with MuSK antibodies (AChR-/MuSK+/LRP4-). Sera from MG patients with agrin antibodies were able to recognize recombinant agrin in conditioned media and in transfected HEK293 cells. These sera also inhibited the agrin-induced MuSK phosphorylation and AChR clustering in muscle cells. Together, these observations indicate that agrin is another autoantigen in patients with MG and agrin autoantibodies may be pathogenic through inhibition of agrin/LRP4/MuSK signaling at the NMJ.
126 citations
TL;DR: Pathologically, cisplatin nephrotoxicity is characterized by cell injury and death in renal tubules, and ideal approaches for renoprotection should not only protect kidneys but also enhance the anticancer efficacy of cisPlatin in chemotherapy.
Abstract: Nephrotoxicity is a major side effect of cisplatin in chemotherapy. Pathologically, cisplatin nephrotoxicity is characterized by cell injury and death in renal tubules. The research in the past decade has gained significant understanding of the cellular and molecular mechanisms of tubular cell death, revealing a central role of mitochondrial dysregulation. The pathological changes in mitochondria in cisplatin nephrotoxicity are mainly triggered by DNA damage response, pro-apoptotic protein attack, disruption of mitochondrial dynamics, and oxidative stress. As such, inhibitory strategies targeting these cytotoxic events may provide renal protection. Nonetheless, ideal approaches for renoprotection should not only protect kidneys but also enhance the anticancer efficacy of cisplatin in chemotherapy.
123 citations
TL;DR: It has been found that low-dose paclitaxel seems promising in treating non-cancer diseases, such as skin disorders, renal and hepatic fibrosis, inflammation, axon regeneration, limb salvage, and coronary artery restenosis.
Abstract: Paclitaxel (Taxol), one of the most important anticancer drugs, has been used for therapy of different types of cancers. Mechanistically, paclitaxel arrests cell cycle and induces cell death by stabilizing microtubules and interfering with microtubule disassembly in cell division. Recently, it has been found that low-dose paclitaxel seems promising in treating non-cancer diseases, such as skin disorders, renal and hepatic fibrosis, inflammation, axon regeneration, limb salvage, and coronary artery restenosis. Future studies need to understand the mechanisms underlying these effects in order to design therapies with specificity.
107 citations
TL;DR: Significant changes of metabolome kidney tissues and plasma in renal IRI are demonstrated and specific metabolites are associated with and may contribute to early injury, shift of energy source, inflammation, and late phase kidney recovery.
Abstract: Changes of metabolism have been implicated in renal ischemia/reperfusion injury (IRI). However, a global analysis of the metabolic changes in renal IRI is lacking and the association of the changes with ischemic kidney injury and subsequent recovery are unclear. In this study, mice were subjected to 25 minutes of bilateral renal IRI followed by 2 hours to 7 days of reperfusion. Kidney injury and subsequent recovery was verified by serum creatinine and blood urea nitrogen measurements. The metabolome of plasma, kidney cortex, and medulla were profiled by the newly developed global metabolomics analysis. Renal IRI induced overall changes of the metabolome in plasma and kidney tissues. The changes started in renal cortex, followed by medulla and plasma. In addition, we identified specific metabolites that may contribute to early renal injury response, perturbed energy metabolism, impaired purine metabolism, impacted osmotic regulation and the induction of inflammation. Some metabolites, such as 3-indoxyl sulfate, were induced at the earliest time point of renal IRI, suggesting the potential of being used as diagnostic biomarkers. There was a notable switch of energy source from glucose to lipids, implicating the importance of appropriate nutrition supply during treatment. In addition, we detected the depressed polyols for osmotic regulation which may contribute to the loss of kidney function. Several pathways involved in inflammation regulation were also induced. Finally, there was a late induction of prostaglandins, suggesting their possible involvement in kidney recovery. In conclusion, this study demonstrates significant changes of metabolome kidney tissues and plasma in renal IRI. The changes in specific metabolites are associated with and may contribute to early injury, shift of energy source, inflammation, and late phase kidney recovery.
96 citations
TL;DR: The impact of diabetes, stroke, and diabetic stroke on cerebral neovascularization is discussed, potential mechanisms involved in diabetes-mediated neov vascularization are explored as well as the effects of the diabetic milieu on poststroke nevascularization and recovery are explored.
Abstract: Neovascularization is an innate physiologic response by which tissues respond to various stimuli through collateral remodeling (arteriogenesis) and new vessel formation from existing vessels (angiogenesis) or from endothelial progenitor cells (vasculogenesis). Diabetes has a major impact on the neovascularization process but the response varies between different organ systems. While excessive angiogenesis complicates diabetic retinopathy, impaired neovascularization contributes to coronary and peripheral complications of diabetes. How diabetes influences cerebral neovascularization remained unresolved until recently. Diabetes is also a major risk factor for stroke and poor recovery after stroke. In this review, we discuss the impact of diabetes, stroke, and diabetic stroke on cerebral neovascularization, explore potential mechanisms involved in diabetes-mediated neovascularization as well as the effects of the diabetic milieu on poststroke neovascularization and recovery, and finally discuss the clinical implications of these effects.
89 citations
TL;DR: The mechanisms by which autophagy protects cells from injury and how, possibly, its pro-survival role switches to pro-death under certain conditions are discussed.
76 citations
TL;DR: Evidence is provided that neuregulin 1 and its receptor ErbB4 tyrosine kinase are critical for maintaining GABAergic activity in amygdala and regulates fear memory.
76 citations
TL;DR: While both inhibition and enhancement of autophagy by pharmacological intervention decreased lesion size and improved neurological scores, the enhancement with rapamycin showed a greater degree of improvement in outcomes as well as in survival.
Abstract: Background and purpose
The role of autophagy in response to ischemic stroke has been confusing with reports that both enhancement and inhibition of autophagy decrease infarct size and improve post-stroke outcomes. We sought to clarify this by comparing pharmacologic modulation of autophagy in two clinically relevant murine models of stroke.
TL;DR: This study demonstrates for the first time that RIPerC therapy is effective in OVX females and prevented the increased mortality during late IV-tPA.
Abstract: Remote ischemic conditioning is neuroprotective in young male rodents after experimental stroke. However, it has never been tested in females whom remain at higher risk of stroke injury after menopause. We tested remote ischemic perconditioning therapy (RIPerC) at 2 h after embolic stroke in ovariectomized (OVX) female mice with and without intravenous tissue plasminogen activator (IV-tPA) treatment. We assessed cerebral blood flow (CBF), neurobehavioral outcomes, infarction, hemorrhage, edema, and survival. RIPerC therapy with and without IV-tPA improved the CBF and neurobehavioral outcomes and reduced the infarction, hemorrhage, and edema significantly. Late IV-tPA alone at 4 h post-stroke neither improved the neurobehavior nor reduced the infarction but aggravated hemorrhage and mortality in OVX mice. RIPerC therapy prevented the increased mortality during late IV-tPA. Our study demonstrates for the first time that RIPerC therapy is effective in OVX females.
TL;DR: SDF-1β provides potent synergistic effects that support B MP-induced local bone formation and thus appears a suitable candidate for optimization of bone augmentation using significantly lower amounts of BMP-2 in spine, orthopedic, and craniofacial settings.
Abstract: Increasing evidence suggests that stromal cell-derived factor-1 (SDF-1/CXCL12) is involved in bone formation, though underlying molecular mechanisms remain to be fully elucidated. Also, contributions of SDF-1β, the second most abundant splice variant, as an osteogenic mediator remain obscure. We have shown that SDF-1β enhances osteogenesis by regulating bone morphogenetic protein-2 (BMP-2) signaling in vitro. Here we investigate the dose-dependent contribution of SDF-1β to suboptimal BMP-2-induced local bone formation; that is, a dose that alone would be too low to significantly induce bone formation. We utilized a critical-size rat calvarial defect model and tested the hypotheses that SDF-1β potentiates BMP-2 osteoinduction and that blocking SDF-1 signaling reduces the osteogenic potential of BMP-2 in vivo. In preliminary studies, radiographic analysis at 4 weeks postsurgery revealed a dose-dependent relationship in BMP-2-induced new bone formation. We then found that codelivery of SDF-1β potentiates sub...
TL;DR: The results suggest that DDR occurs during renal ischemia-reperfusion in vivo and ATP-depletion injury in vitro, and ATM, as a sensor in the DDR, may play a cytoprotective role against tubular cell injury and death.
TL;DR: It is demonstrated that the b-series gangliosides, especially GD3, play a crucial role in the long-term maintenance NSC populations in postnatal mouse brain, and defects of the self-renewal capacity and radial glia-like stem cell outgrowth of postnatal GD3S-KO NSCs could be rescued by restoration of GD3 expression in these cells.
Abstract: The maintenance of a neural stem cell (NSC) population in mammalian postnatal and adult life is crucial for continuous neurogenesis and neural repair. However, the molecular mechanism of how NSC populations are maintained remains unclear. Gangliosides are important cellular membrane components in the nervous system. We previously showed that ganglioside GD3 plays a crucial role in the maintenance of the self-renewal capacity of NSCs in vitro. Here, we investigated its role in postnatal and adult neurogenesis in GD3-synthase knock-out (GD3S-KO) and wild-type mice. GD3S-KO mice with deficiency in GD3 and the downstream b-series gangliosides showed a progressive loss of NSCs both at the SVZ and the DG of the hippocampus. The decrease of NSC populations in the GD3S-KO mice resulted in impaired neurogenesis at the granular cell layer of the olfactory bulb and the DG in the adult. In addition, defects of the self-renewal capacity and radial glia-like stem cell outgrowth of postnatal GD3S-KO NSCs could be rescued by restoration of GD3 expression in these cells. Our study demonstrates that the b-series gangliosides, especially GD3, play a crucial role in the long-term maintenance NSC populations in postnatal mouse brain. Moreover, the impaired neurogenesis in the adult GD3S-KO mice led to depression-like behaviors. Thus, our results provide convincing evidence linking b-series gangliosides deficiency and neurogenesis defects to behavioral deficits, and support a crucial role of gangliosides in the long-term maintenance of NSCs in adult mice.
TL;DR: This broadly targeted intervention strategy led to modest but statistically significant changes in several processes of care, indicating its potential for widespread dissemination to improve end-of-life care for thousands of patients who die each year in inpatient settings.
Abstract: Background
Widespread implementation of palliative care treatment plans could reduce suffering in the last days of life by adopting best practices of traditionally home-based hospice care in inpatient settings.
TL;DR: Future studies with more advanced cell biology or biochemical tools, such as conditional KO mice, may provide further insights into the mechanisms underlying CELSR function, laying the foundation for the design of new CEL SR‐targeted therapeutic reagents.
Abstract: The cadherin epidermal growth factor (EGF) laminin G (LAG) seven-pass G-type receptors (CELSRs) are a special subgroup of adhesion G protein-coupled receptors, which are pivotal regulators of many biologic processes such as neuronal/endocrine cell differentiation, vessel valve formation, and the control of planar cell polarity during embryonic development. All three members of the CELSR family (CELSR1-3) have large ecto-domains that form homophilic interactions and encompass more than 2000 amino acids. Mutations in the ecto-domain or other gene locations of CELSRs are associated with neural tube defects and other diseases in humans. Celsr knockout (KO) animals have many developmental defects. Therefore, specific agonists or antagonists of CELSR members may have therapeutic potential. Although significant progress has been made regarding the functions and biochemical properties of CELSRs, our knowledge of these receptors is still lacking, especially considering that they are broadly distributed but have few characterized functions in a limited number of tissues. The dynamic activation and inactivation of CELSRs and the presence of endogenous ligands beyond homophilic interactions remain elusive, as do the regulatory mechanisms and downstream signaling of these receptors. Given this motivation, future studies with more advanced cell biology or biochemical tools, such as conditional KO mice, may provide further insights into the mechanisms underlying CELSR function, laying the foundation for the design of new CELSR-targeted therapeutic reagents. The cadherin EGF LAG seven-pass G-type receptors (CELSRs) are a special subgroup of adhesion G protein-coupled receptors (GPCRs), which have large ecto-domains that form homophilic interactions and encompass more than 2000 amino acids. Recent studies have revealed that CELSRs are pivotal regulators of many biological processes, such as neuronal/endocrine cell differentiation, vessel valve formation and the control of planar cell polarity during embryonic development.
TL;DR: Deletion of the arginase 2 gene protected against hyperoxia-induced vaso-obliteration, enhanced physiological vascular repair, and reduced retinal neovascularization in the OIR model.
Abstract: Background: Hyperoxia exposure of premature infants causes obliteration of the immature retinal microvessels, leading to a condition of proliferative vitreoretinal neovascularization termed retinopathy of prematurity (ROP). Previous work has demonstrated that the hyperoxia-induced vascular injury is mediated by dysfunction of endothelial nitric oxide synthase resulting in peroxynitrite formation. This study was undertaken to determine the involvement of the ureahydrolase enzyme arginase in this pathology. Methods and Findings: Studies were performed using hyperoxia-treated bovine retinal endothelial cells (BRE) and mice with oxygen-induced retinopathy (OIR) as experimental models of ROP. Treatment with the specific arginase inhibitor 2(S)amino-6-boronohexanoic acid (ABH) prevented hyperoxia-induced apoptosis of BRE cells and reduced vaso-obliteration in the OIR model. Furthermore, deletion of the arginase 2 gene protected against hyperoxia-induced vaso-obliteration, enhanced physiological vascular repair, and reduced retinal neovascularization in the OIR model. Additional deletion of one copy of arginase 1 did not improve the vascular pathology. Analyses of peroxynitrite by quantitation of its biomarker nitrotyrosine, superoxide by dihydroethidium imaging and NO formation by diaminofluoroscein imaging showed that the protective actions of arginase 2 deletion were associated with blockade of superoxide and peroxynitrite formation and normalization of NOS activity. Conclusions: Our data demonstrate the involvement of arginase activity and arginase 2 expression in hyperoxia-induced vascular injury. Arginase 2 deletion prevents hyperoxia-induced retinal vascular injury by preventing NOS uncoupling resulting in decreased reactive oxygen species formation and increased nitric oxide bioavailability.
TL;DR: Aβ1–42 upregulates NSC proliferation by modulating the expression of several glycogenes involved in Notch signaling, including fucosyltransferase IX (FUT9), sialyl transferase III (ST-III), glucosylceramide ceramidase (GLCC), and mitochondrial sialidases (Neu4).
Abstract: Amyloid β-peptides (Aβs) aggregate to form amyloid plaques, also known as senile plaques, which are a major pathological hallmark of Alzheimer’s disease (AD). Aβs are reported to possess proliferation effects on neural stem cells (NSCs); however, this effect remains controversial. Thus, clarification of their physiological function is an important topic. We have systematically evaluated the effects of several putative bioactive Aβs (Aβ1–40, Aβ1–42, and Aβ25–35) on NSC proliferation. Treatment of NSCs with Aβ1–42 significantly increased the number of those cells (149 ± 10 %). This was not observed with Aβ1–40 which did not have any effects on the proliferative property of NSC. Aβ25–35, on the other hand, exhibited inhibitory effects on cellular proliferation. Since cell surface glycoconjugates, such as glycolipids, glycoproteins, and proteoglycans, are known to be important for maintaining cell fate determination, including cellular proliferation, in NSCs and they undergo dramatic changes during differentiation, we examined the effect of Aβs on a number of key glycoconjugate metabolizing enzymes. Significantly, we found for the first time that Aβ1–42 altered the expression of several key glycosyltransferases and glycosidases, including fucosyltransferase IX (FUT9), sialyltransferase III (ST-III), glucosylceramide ceramidase (GLCC), and mitochondrial sialidase (Neu4). FUT9 is a key enzyme for the synthesis of the Lewis X carbohydrate epitope, which is known to be expressed in stem cells. Aβ1–42 also stimulated the Notch1 intracellular domain (NICD) by upregulation of the expression of Musashi-1 and the paired box protein, Pax6. Thus, Aβ1–42 upregulates NSC proliferation by modulating the expression of several glycogenes involved in Notch signaling.
TL;DR: It is suggested that VPS35 is necessary for mouse RGC survival and regeneration, and Vps35-deficiency may contribute to the pathogenesis of retinal ganglion neuro-degeneration, a critical pathology leading to the blindness of many retinal degenerative disorders.
Abstract: VPS35 (vacuolar protein sorting 35) is a major component of retromer that selectively promotes endosome-to-Golgi retrieval of transmembrane proteins. Dysfunction of retromer is a risk factor for the pathogenesis of Parkinson’s disease (PD) and Alzheimer’s disease (AD), both neuro-degeneration disorders. However, VPS35/retromer’s function in retina or the contribution of Vps35-deficiency to retinal neuro-degenerative disorders has not been investigated. Here we provide evidence for a role of VPS35 in mouse retinal ganglion cell (RGC) survival and regeneration. VPS35 is selectively expressed in developing mouse RGCs. RGCs from young adult Vps35 heterozygotes (Vps35+/m) show degenerative-like features, such as dystrophic dendrites, reduced axon fibers, and increased TUNEL labeled RGCs. Additionally, gliosis in the optic nerve is transiently elevated in neonatal, but reduced in aged Vps35+/m mice. Optic nerve injury-induced gliosis is also attenuated in Vps35+/m mice. These results suggest that Vps35 is necessary for mouse RGC survival and regeneration, and Vps35-deficiency may contribute to the pathogenesis of retinal ganglion neuro-degeneration, a critical pathology leading to the blindness of many retinal degenerative disorders.
TL;DR: The results suggest that caspase-14 contributes to RPE cell barrier disruption under hyperglycemic conditions and thus plays a role in the development of diabetic macular edema.
Abstract: We recently showed that caspase-14 is a novel molecule in retina with potential role in accelerated vascular cell death during diabetic retinopathy (DR). Here, we evaluated whether caspase-14 is implicated in retinal pigment epithelial cells (RPE) dysfunction under hyperglycemia. The impact of high glucose (HG, 30 mM D-glucose) on caspase-14 expression in human RPE (ARPE-19) cells was tested, which showed significant increase in caspase-14 expression compared with normal glucose (5 mM D-glucose + 25 mM L-glucose). We also evaluated the impact of modulating caspase-14 expression on RPE cells barrier function, phagocytosis, and activation of other caspases using ARPE-19 cells transfected with caspase-14 plasmid or caspase-14 siRNA. We used FITC-dextran flux assay and electric cell substrate impedance sensing (ECIS) to test the changes in RPE cell barrier function. Similar to HG, caspase-14 expression in ARPE-19 cells increased FITC-dextran leakage through the confluent monolayer and decreased the transcellular electrical resistance (TER). These effects of HG were prevented by caspase-14 knockdown. Furthermore, caspase-14 knockdown prevented the HG-induced activation of caspase-1 and caspase-9, the only activated caspases by HG. Phagocytic activity was unaffected by caspase-14 expression. Our results suggest that caspase-14 contributes to RPE cell barrier disruption under hyperglycemic conditions and thus plays a role in the development of diabetic macular edema.
TL;DR: This result represents the first demonstration of opposite effects of different species of a single class of phospholipid and suggests that different PG species may signal to diverse effector enzymes to differentially affect keratinocyte proliferation and normalize keratinocytes proliferation, which may be useful for treating skin diseases characterized by excessive or insufficient proliferation.
Abstract: We have previously shown that liposomes composed of egg-derived phosphatidylglycerol (PG), with a mixed fatty acid composition (comprising mainly palmitate and oleate), inhibit the proliferation and promote the differentiation of rapidly dividing keratinocytes, and stimulate the growth of slowly proliferating epidermal cells. To determine the species of PG most effective at modulating keratinocyte proliferation, primary mouse keratinocytes were treated with different PG species, and proliferation was measured. PG species containing polyunsaturated fatty acids were effective at inhibiting rapidly proliferating keratinocytes, whereas PG species with monounsaturated fatty acids were effective at promoting proliferation in slowly dividing cells. Thus, palmitoyl-arachidonyl-PG (16∶0/20∶4), palmitoyl-linoleoyl-PG (16∶0/18∶2), dilinoleoyl-PG (18∶2/18∶2) and soy PG (a PG mixture with a large percentage of polyunsaturated fatty acids) were particularly effective at inhibiting proliferation in rapidly dividing keratinocytes. Conversely, palmitoyl-oleoyl-PG (16∶0/18∶1) and dioleoyl-PG (18∶1/18∶1) were especially effective proproliferative PG species. This result represents the first demonstration of opposite effects of different species of a single class of phospholipid and suggests that these different PG species may signal to diverse effector enzymes to differentially affect keratinocyte proliferation and normalize keratinocyte proliferation. Thus, different PG species may be useful for treating skin diseases characterized by excessive or insufficient proliferation.
TL;DR: High and low levels of ionized serum calcium concentration can produce characteristic changes on the electrocardiogram, but these changes are almost entirely limited to the duration of the ST segment, with no change in the QRS complexes or T waves.
Abstract: High and low levels of ionized serum calcium concentration can produce characteristic changes on the electrocardiogram. These changes are almost entirely limited to the duration of the ST segment, with no change in the QRS complexes or T waves. High ionized serum calcium shortens the ST segment, and low ionized serum calcium prolongs the ST segment. Two common clinical scenarios are presented.
TL;DR: The data demonstrate that the aromatic amino acids down-regulated early and late osteoclastic differentiation markers as measured by real time PCR, and suggest a link between the vitronectin receptor and the secreted cathepsin K that both showed consistent effects to the aromatic acids treatment.
Abstract: We had shown that aromatic amino acid (phenylalanine, tyrosine, and tryptophan) supplementation prevented bone loss in an aging C57BL/6 mice model. In vivo results from the markers of bone breakdown suggested an inhibition of osteoclastic activity or differentiation. To assess osteoclastic differentiation, we examined the effects of aromatic amino acids on early /structural markers as vitronectin receptor, calcitonin receptor, and carbonic anhydrase II as well as, late/functional differentiation markers; cathepsin K and matrix metalloproteinase 9 (MMP-9). Our data demonstrate that the aromatic amino acids down-regulated early and late osteoclastic differentiation markers as measured by real time PCR. Our data also suggest a link between the vitronectin receptor and the secreted cathepsin K that both showed consistent effects to the aromatic amino acid treatment. However, the non-attachment related proteins, calcitonin receptor, and carbonic anhydrase II, demonstrated less consistent effects in response to treatment. Our data are consistent with aromatic amino acids down-regulating osteoclastic differentiation by suppressing remodeling gene expression thus contributing initially to the net increase in bone mass seen in vivo.
TL;DR: It is concluded that HSBp1 plays an essential role during early mouse and zebrafish embryonic development and a potential role for HSBP1 in the Wnt pathway is suggested.
Journal Article•
01 Nov 2014-Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists
TL;DR: C-ECT and continuation pharmacotherapy may be more effective than either alone for preventing relapse, however, more definitive randomized clinical trials are needed.
Abstract: Background One-third of patients who suffer from depression are resistant to conventional treatments. An acute course of electroconvulsive therapy (ECT) can lead to remission of depressive symptoms in a substantial portion of the treatment-resistant patients. However, prevention of relapse with depressive symptoms after the index course of ECT can be challenging. We review pertinent studies on the topic and analyze the best strategies to avoid relapse and recurrence of depressive symptoms. Methods We performed a systematic literature review of PubMed through April 2014 for clinical trials published in English to determine if continuation ECT (C-ECT), continuation medication, continuation psychotherapy, or combinations of these are the best strategy to avoid relapse and recurrence of depressive symptoms after an acute course of ECT. Clinical trials comparing ≥2 of the above strategies were included in the review. Results Although there are few rigorous randomized clinical trials in this area, most studies suggest that combined C-ECT and continuation pharmacotherapy are the most effective strategy in relapse prevention. Conclusions C-ECT and continuation pharmacotherapy may be more effective than either alone for preventing relapse. However, more definitive randomized clinical trials are needed.
TL;DR: It is found that TBI is permissive for transplanted BMSCs to engraft and contribute to new bone formation, and investigated the potential role of SDF-1 in facilitating these events.
Abstract: Skeletal injury is a major clinical challenge accentuated by the decrease of bone marrow-derived mesenchymal stem/stromal cells (BMSCs) with age or disease. Numerous experimental and clinical studi...
TL;DR: The results suggest that manipulation of mitofusins may provide a novel therapeutic advantage in treating prostate cancer and that downregulation of Mfn1 by siRNA enhanced the apoptotic response of LNCaP cells to CGP, suggesting a likely pro-survival role for Mfn 1 in these cells.
Abstract: Mitochondria constantly divide (mitochondrial fission) and fuse (mitochondrial fusion) in a normal cell. Disturbances in the balance between these two physiological processes may lead to cell dysfunction or to cell death. Induction of cell death is the prime goal of prostate cancer chemotherapy. Our previous study demonstrated that androgens increase the expression of a mitochondrial protein involved in fission and facilitate an apoptotic response to CGP37157 (CGP), an inhibitor of mitochondrial calcium efflux, in prostate cancer cells. However, the regulation and role of mitochondrial fusion proteins in the death of these cells have not been examined. Therefore, our objective was to investigate the effect of CGP on a key mitochondrial fusion protein, mitofusin 1 (Mfn1), and the role of Mfn1 in prostate cancer cell apoptosis. We used various prostate cancer cell lines and western blot analysis, qRT-PCR, siRNA, M30 apoptosis assay and immunoprecipitation techniques to determine mechanisms regulating Mfn1. Treatment of prostate cancer cells with CGP resulted in selective degradation of Mfn1. Mfn1 ubiquitination was detected following immunoprecipitation of overexpressed Myc-tagged Mfn1 protein from CGP-treated cells, and treatment with the proteasomal inhibitor lactacystin, as well as siRNA-mediated knockdown of the E3 ubiquitin ligase March5, protected Mfn1 from CGP-induced degradation. These data indicate the involvement of the ubiquitin-proteasome pathway in CGP-induced degradation of Mfn1. We also demonstrated that downregulation of Mfn1 by siRNA enhanced the apoptotic response of LNCaP cells to CGP, suggesting a likely pro-survival role for Mfn1 in these cells. Our results suggest that manipulation of mitofusins may provide a novel therapeutic advantage in treating prostate cancer.
TL;DR: The results showed that despite comparable VEGF level and signal in TKO, exposure to hyperoxia significantly decreased Trx expression compared to WT and resulted in liberation and activation of the apoptotic ASK-1 signal.
Abstract: We have recently shown that thioredoxin interacting protein (TXNIP) is required for VEGF-mediated VEGFR2 receptor activation and angiogenic signal. Retinas from TXNIP knockout mice (TKO) exhibited higher cellular antioxidant defense compared to wild type (WT). This study aimed to examine the impact of TXNIP deletion on hyperoxia-induced vaso-obliteration in ischemic retinopathy. TKO and WT pups were subjected to oxygen-induced retinopathy model. Retinal central capillary dropout was measured at p12. Retinal redox and nitrative state were assessed by reduced-glutathione (GSH), thioredoxin reductase activity and nitrotyrosine formation. Western blot and QT-PCR were used to assess VEGF, VEGFR-2, Akt, iNOS and eNOS, thioredoxin expression, ASK-1 activation and downstream cleaved caspase-3 and PARP in retinal lysates. Retinas from TKO mice exposed to hyperoxia showed significant increases (1.5-fold) in vaso-obliteration as indicated by central capillary drop out area compared to WT. Retinas from TKO showed minimal nitrotyrosine levels (10% of WT) with no change in eNOS or iNOS mRNA expression. There was no change in levels of VEGF or activation of VEGFR2 and its downstream Akt in retinas from TKO and WT. In comparison to WT, retinas from TKO showed significantly higher level of GSH and thioredoxin reductase activity in normoxia but comparable levels under hyperoxia. Exposure of TKO to hyperoxia significantly decreased the anti-apoptotic thioredoxin protein (∼50%) level compared with WT. This effect was associated with a significant increase in activation of the apoptotic ASK-1, PARP and caspase-3 pathway. Our results showed that despite comparable VEGF level and signal in TKO, exposure to hyperoxia significantly decreased Trx expression compared to WT. This effect resulted in liberation and activation of the apoptotic ASK-1 signal. These findings suggest that TXNIP is required for endothelial cell survival and homeostasis especially under stress conditions including hyperoxia.
TL;DR: This chapter discusses the expression profiles and potential functional roles of glycoconjugates during neural development, which play crucial functional roles in cell proliferation, differentiation, interaction, migration, and signal transduction.
Abstract: In mammals, the central and peripheral nervous systems are developmentally derived from cells in the neural plate. Specific ectodermal cells in this area form the neural tube and neural crest during the early developmental stage. The neural tube is the origin of the central nervous system which consists of both the brain and spinal cord, whereas neural crest cells are precursors of the peripheral nervous system. During neural tube formation and neural crest development, carbohydrate-rich molecules, including glycolipids, glycoproteins, and proteoglycans, are expressed primarily on the outer surface of cell plasma membranes. The structural diversity of their carbohydrate moieties coupled with their expression at different stages of development makes these molecules excellent biomarkers for various cell types. In addition, these molecules play crucial functional roles in cell proliferation, differentiation, interaction, migration, and signal transduction. In this chapter, we discuss the expression profiles and potential functional roles of glycoconjugates during neural development.